CN102311512B - Cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof - Google Patents
Cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof Download PDFInfo
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Abstract
The invention provides a cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and a preparation method thereof. The cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer has a structural formula shown in a formula (1), wherein m in the formula (1) is an integral number of between 6 and 8, and G is oxygen atoms or a structure shown in the specification (-O-CH2-CH(CH3)-O-).
Description
Technical field
The present invention relates to a kind of cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof.
Background technology
Cyclodextrin is six macrocylc compound that above D-glucopyranose units is formed by connecting from beginning to end with Isosorbide-5-Nitrae-glycosidic link that obtain from starch, common α-, β-and γ- cyclodextrin 6,7 and 8 glucose units are arranged respectively.Because each glucopyranose units is C
1Chair conformation, whole molecule are truncated cones shape cavity configuration.All secondary hydroxyls are the interarea that 6 hydroxyls of glucose unit have consisted of the frustum-like shape structure.Surface of internal cavity is by C
3And C
5On hydrogen atom and the Sauerstoffatom on the glycosidic link consist of, so inner chamber is hydrophobic environment, the outside because of the gathering of hydroxyl form wetting ability (Jin Hui, Li Fang, Gu Junling, Fu Ruonong, Liu Yu, Dai Rongji, analytical chemistry, 1996,24(12): 1387).The amphipathic structure of this uniqueness can make cyclodextrin as different hydrophobicity " object " compound of " main body " inclusion.The unique texture of cyclodextrin makes them form host and guest's structure or to form clathrate with many kinds of substance.Cyclodextrin is widely used in pharmacy, can prevent drug volatilization, increase solubleness, improve bioavailability, the prolong drug transformation period, improve drug effect, reduce medicine irritation toxicity, side effect, cover (the Fujiwara T such as unpleasant odor, Tanaka N, Kobayashl S.Chem.Lett., 1990:739).
Cyclodextrin is its outstanding " embedding " effect in the topmost embodiment of application pharmaceutically, namely utilize the character of its hollow, some chemicalses " absorption " with strong bitter taste, sharp flavor or irritating smell are entered in its hollow capsule body, make it to become a kind of tasteless powder.Secondly, cyclodextrin can also adsorb the oily maters such as fish oil, vitamin-E, vitamin A and beta carotene, and makes it become powder agent, thereby has greatly expanded their Application Areas.
In addition, cyclodextrin can produce sterically hindered layer, thereby weaken the opsonization of the effect of various compositions in the blood, particularly plasma proteins and RES(reticuloendothelial cell subsequently) the picked-up effect, the simultaneously exchange of lipoprotein, the hydrolysis of Phospholipid hydrolase etc. all are subject to establishment; Improve the film surface hydrophilicity: cyclodextrin-aliphatic polyester-phospholipid polyalcohol has very long polar group, can improve the wetting ability of carrier surface, thereby improved the MPS(macrophage system) it is absorbed the energy barrier of destruction, effectively stop the opsonization of carrier surface and plasma proteins, and reduced the affinity interaction of the MPS of carrier.Because the existence of cyclodextrin so that this kind material during as carrier ligands bound thereto material in vivo and in vitro stability very large change has been arranged, increase redispersibility; Prolong the time in the body circulation, can reduce speed and the degree absorbed by MPS, and reduced the untoward reaction to this main host system of defense.But cyclodextrin can not form separately micella as the auxiliary material of medicine.
Phosphatidylethanolamine is a kind of of phospholipid, also once claims kephalin (KepHa-Lin).In the existing phosphatide, the content of phosphatidylethanolamine is only second to Yelkin TTS in organic sphere, and in colibacillus, it accounts for 80% of total phospholipids.Phosphatide is biomembranous important component, is the basic substance of the activity of sustaining life.
Aliphatic polyester is to obtain the biodegradable polymer that the drugs approved by FDA approval can enter human body such as poly(lactic acid) (PLA), polymeric polyglycolide-polylactide (PLGA), polycaprolactone (PCL).They are good biocompatibility, biodegradable polymkeric substance in vivo, therefore are suitable for very much as drug carrier material, and (A.Lucke is widely used at the aspects such as control release of artificial skin and organizational project, medicine, Biomaterials, 2000,21,2361.; J.Hermann, R.Bodmeier, Int.J.Pharm., 1995,126,129.).Yet the wetting ability of these aliphatic polyesters is poor, has high crystalline, and degradation speed is slow.In the aliphatic polyester segment, introduce biocompatibility and the good segment of blood compatibility, the performance of aliphatic polyester is had greatly improved.
As everyone knows, if having simultaneously hydrophilic and hydrophobic two portions in the polymer substance forms, so this amphipathy macromolecule material just can be assembled the formation polymer nanoparticle in the aqueous solution, be by amphipathy macromolecule material spontaneous a kind of self-assembled structures that forms in the aqueous solution, and the wetting ability fragment forms shell, the hydrophobicity fragment forms kernel, form unique nucleocapsid structure (Adams ML, Lavasanifar A, Kwon GS.J.Pharm.Sci., 2003,92(7): 1343).This nucleocapsid structure has that drug loading height, medicine carrying scope are wide, distribute in long, the unique body of residence time in the good stability, body and increase medicine stability, improve bioavailability and reduce characteristics (the Kakizawa Y such as toxic side effect, Kataoka K.Adv.Drug.Deliv.Rev., 2002,54(2): 203-22.).
The characteristics such as nucleocapsid structure, micelle-forming concentration are low, Heat stability is good are with a wide range of applications in fields such as drug delivery systems amphipathy macromolecule material nano-micelle because having.The nearly more than ten years, the nanoparticle drug delivery system that is comprised of the amphiphilic macromolecular material is with its advantage of giving prominence to and the extensive concern that has been subject to international the world of medicine in the very big application prospect of the aspects such as tumour medicine, genomic medicine, infection medicine and biological diagnosis.Amphiphilic high molecular nanometer plastochondria system is the maximum and the most ripe polymeric colloid drug delivery system of at present research.Studies show that in a large number, because the carrier of amphiphilic polymer substance drug delivery system can self aggregation becomes the micella of unique nucleocapsid structure.Because " nuclear-shell " similar that polymer micelle has is lipoprotein and viral structure in organism, has in some sense certain bio-imitability, and the higher stability of polymer substance nano-micelle has determined that it still can stable existence when concentration is extremely rare, the wetting ability shell of micellar surface can reduce scavenger cell to identification and the phagocytic activity of particle, prolong its cycling time in blood, can protect medicine to exempt from the destruction of physiological environment, slowly discharge in vivo; The particle diameter of micella is little, can directly enter organ and cell interior by capillary vessel, by more effective absorption; The extensive administering mode of micelle administration system is that other any formulation is all incomparable, and it can enter blood circulation of human body system etc. by oral, the modes such as injection (intravenous injection, intramuscular injection, subcutaneous injection), transdermal and have remarkable advantage.
Summary of the invention
The present invention can not form micella separately in order to overcome cyclodextrin, and the shortcoming such as the aliphatic polyester hydrophobicity is strong, and a kind of novel amphipathic cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof that has is provided.
The invention provides a kind of cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer, the structural formula of described cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer is as shown in the formula shown in (1),
M is the integer of 6-8 in the formula (1), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, E are the structure by following formula (2) expression,
L is that R and R ' represent that all carbonatoms is the alkyl of 5-21 by the aliphatic poly ester structure of formula (3), formula (4) or formula (5) expression in the formula (2), and R and R ' are identical or different,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240.
The present invention also provides the preparation method of cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer, and the method may further comprise the steps:
(a) in the presence of organic amine, in the first organic solvent, ester is contacted with cyclodextrin, obtain by the cyclodextrin shown in the formula (6)-aliphatic polyester graftomer, described the first organic solvent is the solvent that can dissolve cyclodextrin and ester, and described cyclodextrin is to be selected from a kind of in alpha-cylodextrin, beta-cyclodextrin, hydroxypropylβ-cyclodextrin or the γ-cyclodextrin; Described ester is one or both in rac-Lactide, glycollide and the caprolactone;
M is the integer of 6-8 in formula (6), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, L are the aliphatic poly ester structure by formula (3), formula (4) or formula (5) expression,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240;
(b) in the presence of nitrogenous heteroatomic 6-membered heterocyclic compound, in the second organic solvent, described cyclodextrin-aliphatic polyester graftomer is contacted with 4-oil of mirbane chloro-formic ester, obtain by the cyclodextrin-aliphatic polyester shown in the formula (7)-4-oil of mirbane chloro-formic ester graftomer, described the second organic solvent is the solvent that can dissolve cyclodextrin-aliphatic polyester graftomer and 4-oil of mirbane chloro-formic ester;
M is the integer of 6-8 in formula (7), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, L are that A is the structure by formula (8) expression by the aliphatic poly ester structure of formula (3), formula (4) or formula (5) expression,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240;
(c) in the presence of organic amine, in the 3rd organic solvent, after making described cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer and phosphatidylethanolamine contacting, with products therefrom and Tris-HCl(Tri(Hydroxymethyl) Amino Methane Hydrochloride) buffered soln contacts, obtain by the cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer shown in the formula (1), described the 3rd organic solvent is the solvent that can dissolve cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer and phosphatidylethanolamine, described phosphatidylethanolamine is for being selected from DPPE, a kind of in two grease acyl phosphatidylethanolamines or the DSPE
M is the integer of 6-8 in the formula (1), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, E are the structure by following formula (2) expression,
L is that R and R ' represent that all carbonatoms is the alkyl of 5-21 by the aliphatic poly ester structure of formula (3), formula (4) or formula (5) expression in the formula (2), and R and R ' are identical or different,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240.
Cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer among the present invention has simultaneously hydrophilic and hydrophobic two portions and forms, and hydrophilic segment is the cyclodextrin part, and hydrophobic part is aliphatic polyester and phosphatidylethanolamine part.Because phosphatidylethanolamine is a kind of of phospholipid, aliphatic polyester, to obtain the aliphatic polyester that drugs approved by FDA approval can enter human body such as poly(lactic acid) (PLA), polymeric polyglycolide-polylactide (PLGA), polycaprolactone (PCL), therefore, compare with existing cyclodextrin derivative, cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer biocompatibility of the present invention is effective.Owing to itself contain phosphatide in the human body, so being easy to human body, the nanoparticle as the cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer of pharmaceutical carrier among the present invention accepts, can carry out metabolism at human body.This amphipathic derivatives can be self-assembled into the nano-micelle of cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer in the aqueous solution, hydrophilic segment forms shell, and hydrophobic fragment forms kernel, consists of unique nucleocapsid structure.Because cyclodextrin has biological degradability and wetting ability, aliphatic polyester, phosphatidylethanolamine have hydrophobicity, so with the nano-micelle of amphipathic cyclodextrin-aliphatic polyester-phosphatidylethanolamine graftomer as pharmaceutical carrier, can effectively prolong drug effect, reduce toxicity, improve bioavailability and biological activity.Therefore, the preparation method of this cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer among the present invention is with a wide range of applications.
Description of drawings
Fig. 1 represents the transmission electron microscope picture of the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle among the embodiment 1.
Fig. 2 represents the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle scattering of light synoptic diagram among the embodiment 1.
The infrared spectrogram of the hydroxypropylβ-cyclodextrin among Fig. 3 (a) expression embodiment 1.The infrared spectrogram of the hydroxypropylβ-cyclodextrin among Fig. 3 (b) expression embodiment 1-poly(lactic acid) graftomer.The infrared spectrogram of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 3 (c) expression embodiment 1-4-oil of mirbane chloro-formic ester graftomer.The infrared spectrogram of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 3 (d) expression embodiment 1-DPPE graftomer.
The proton nmr spectra of the hydroxypropylβ-cyclodextrin among Fig. 4 (a) expression embodiment 1; The proton nmr spectra of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 4 (b) expression embodiment 1-DPPE graftomer; The carbon-13 nmr spectra of the hydroxypropylβ-cyclodextrin among Fig. 4 (c) expression embodiment 1; The carbon-13 nmr spectra of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 4 (d) expression embodiment 1-DPPE graftomer.
The nucleus magnetic resonance phosphorus spectrogram of the DPPE among Fig. 5 (a) expression embodiment 1; The nucleus magnetic resonance phosphorus spectrogram of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 5 (b) expression embodiment 1-DPPE graftomer.
Fig. 6 represents the fluorescence spectrum figure of the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle among the embodiment 1, and wherein a-f represents respectively the fluorescence emission spectrum of pyrene in the aqueous solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) that concentration is 0.001mg/ml, 0.0004mg/ml, 0.0002mg/ml, 0.00008mg/ml, 0.00002mg/ml, 0.000001mg/ml-DPPE graftomer.
Fig. 7 represents the micelle-forming concentration figure of the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle among the embodiment 1.
Embodiment
According to the present invention, the weight-average molecular weight of described cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer is 4000-100000Da, and described cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer can form the nanoparticle that particle diameter is 80-150nm.
According to preparation method provided by the invention, described contact in the step (a) is carried out under inert atmosphere, the condition of described contact comprises: the mol ratio of described ester and described cyclodextrin is 1-15:1, with respect to the 1g cyclodextrin, the consumption of described organic amine is 0.01-5ml, the consumption of described the first organic solvent is 4-100ml, and the temperature of contact is 70-85 ℃, and the time of contact is 10-15 hour.
Because rac-Lactide, glycollide and caprolactone open loop under the effect of catalyzer, can be directly and on the cyclodextrin-OH reacts.Therefore, select in the present invention and in rac-Lactide, glycollide and the caprolactone one or both are directly contacted with cyclodextrin and obtain by the cyclodextrin shown in the formula (6)-aliphatic polyester graftomer.The rac-Lactide that uses among the present invention, glycollide, caprolactone are commercially available commodity.
According to preparation method provided by the invention, in the step (b), described nitrogenous heteroatomic 6-membered heterocyclic compound is DMAP and pyridine, the condition of described contact comprises: the weight ratio of described cyclodextrin-aliphatic polyester graftomer and described 4-oil of mirbane chloro-formic ester is 5-20:1, the weight ratio of described cyclodextrin-aliphatic polyester graftomer and described DMAP is 20-60:1, with respect to the described cyclodextrin of 1g-aliphatic polyester graftomer, the consumption of described pyridine is 0.2-2ml, the consumption of described the second organic solvent is 3-12ml, the temperature of contact is-10 ℃ to 0 ℃, and the time of contact is 6-10 hour.
According to preparation method provided by the invention, described contact in the step (c) all is that lucifuge is carried out under inert atmosphere, the condition that cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer contacts with phosphatidylethanolamine comprises: the weight ratio of described cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer and described phosphatidylethanolamine is 5-50:1, with respect to the described cyclodextrin-aliphatic polyester of 1g-4-oil of mirbane chloro-formic ester graftomer, the consumption of described organic amine is 0.05-0.3ml, the consumption of described the 3rd organic solvent is 8-18ml, the temperature that cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer contacts with phosphatidylethanolamine is 20-30 ℃, and cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer and phosphatidylethanolamine duration of contact are 15-20 hour;
With respect to the described product of 1g, the pH of described Tris-HCl buffered soln is 8-9, and consumption is 8-70ml, and the temperature that products therefrom contacts with Tris-HCl buffered soln is 4-25 ℃, and products therefrom and Tris-HCl buffered soln duration of contact are 15-20 hour.
Under the preferable case, comprise also that in preparation method's provided by the invention step (a) the first organic solvent in the products therefrom was removed after described ester contacted with cyclodextrin, the product that to remove afterwards behind the first organic solvent precipitates in water, obtain solid product, again the gained solid product is washed successively with drying after again with toluene or benzene extracting, with the solid after the extracting at 20-30 ℃ of lower vacuum-drying 24-48 hour.
Under the preferable case, comprise also that in preparation method's provided by the invention step (b) the second organic solvent in the products therefrom was removed after described cyclodextrin-aliphatic polyester graftomer contacted with 4-oil of mirbane chloro-formic ester, the product that to remove afterwards behind the second organic solvent precipitates in ether/sherwood oil mixing solutions, obtain solid product, again the gained solid product is washed with ether/sherwood oil mixing solutions, at 20-30 ℃ of lower vacuum-drying 24-48 hour.
Under the preferable case, in preparation method's provided by the invention step (c), also comprise the second organic solvent in the described product is removed, the product that to remove afterwards behind the second organic solvent precipitates in ether/sherwood oil mixing solutions, obtain solid product, again with the gained solid product at 20-30 ℃ of lower vacuum-drying 24-48 hour.
Under the preferable case, comprise also in preparation method's provided by the invention step (c) described cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer put into dialysis tubing that the lucifuge dialysis is 24-48 hour in 4-25 ℃ distilled water.
In the present invention, described organic amine is preferably triethylamine, described the first organic solvent is preferably dimethyl sulfoxide (DMSO), described nitrogenous heteroatomic 6-membered heterocyclic compound is preferably DMAP and pyridine, described the second organic solvent is preferably chloroform or methylene dichloride, and described the 3rd organic solvent is preferably chloroform or methylene dichloride.And there is no particular limitation to the ether in described ether/sherwood oil mixing solutions and the volume ratio of sherwood oil in the present invention, but preferred 1-4:1.Described inert atmosphere can be nitrogen atmosphere or zero group atmosphere, preferred nitrogen atmosphere.Hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle can be preserved in freeze-drying.
Take hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer as example, step (a) is as follows to the reaction scheme of step (d), and wherein n is the integer of 12-240.
Specify the present invention below in conjunction with embodiment.
N value in following examples calculates by feed ratio.
Weight-average molecular weight in following examples is to record by the gel permeation chromatography of the U.S. this 515+2410 of water (GPC), and solvent is tetrahydrofuran (THF).
Hydroxypropylβ-cyclodextrin in following examples, hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer, hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester graftomer, hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer are carried out infrared spectra (U.S. Perkin-Elmer Corporations, model is Spectrum one) to be detected.
Hydroxypropylβ-cyclodextrin in following examples, hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer are carried out proton nmr spectra and carbon-13 nmr spectra (Switzerland, Brooker company, model is AV400) detect, the proton nmr spectra of hydroxypropylβ-cyclodextrin and the testing conditions of carbon-13 nmr spectra comprise: dimethyl sulfoxide (DMSO) is interior mark, and solvent for use is deuterated dimethyl sulfoxide; The proton nmr spectra of hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE and the testing conditions of carbon-13 nmr spectra comprise that chloroform is interior mark, and solvent is deuterochloroform.
DPPE in following examples, hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer are carried out nucleus magnetic resonance phosphorus spectrum (Switzerland, Brooker company, model is AV400) detect, the testing conditions of the nucleus magnetic resonance phosphorus spectrum of two palmityl phosphatidyl ethanol comprises: dimethyl sulfoxide (DMSO) is interior mark, and solvent for use is deuterated dimethyl sulfoxide; The testing conditions of the nucleus magnetic resonance phosphorus spectrum of hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE comprises that chloroform is interior mark, and solvent is deuterochloroform.
Resulting hydroxypropylβ-cyclodextrin-poly(lactic acid) in following examples-DPPE graftomer nanoparticle is carried out dynamic light scattering (Zetasizer NanoZS), transmission electron microscope (U.S. FEI, Tecnai G2 20S-TWIN, 200kV) and fluorescence spectrum (U.S. Perkin-Elmer Corporations, model is LS-55) to measure and observe.
Synthesizing of hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer
(1) with rac-Lactide (the Alfar Aesar company of 11.28g; 97%; analytical pure) and the hydroxypropylβ-cyclodextrin of 0.5g (Japanese Sigma-Aldrich company) place there-necked flask; after vacuumizing 1 hour, the dmso solution after the distillation of adding 20mL adds 1.5mL triethylamine (chemical plant, Gansu Province, west, Shantou, Guangdong city; analytical pure); at 85 ℃, reaction is 10 hours under the nitrogen protection, obtains hydroxypropylβ-cyclodextrin-thick product of poly(lactic acid) graftomer.Then precipitate with 300mL water, washing (150mL * 3 time), drying is 36 hours in 25 ℃ of vacuum drying oven casees, and then with toluene extracting (30mL * 2 time), drying is 36 hours in 25 ℃ of vacuum drying ovens, obtain solid product hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer 8.84g, as calculated n=140.
(2) hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer 2.0g is joined in the 6mL chloroform chloroformic solution of preparation hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer; The 4-oil of mirbane chloro-formic ester (Alfar Aesar company, 97%) of 0.4g and the DMAP (Alfar Aesar company, 99%) of 0.04g are dissolved preparation 4-oil of mirbane chloro-formic ester and DMAP chloroformic solution with the 6mL chloroform; The 4-oil of mirbane chloro-formic ester of 6mL and the mixing chloroformic solution of DMAP are added drop-wise in the chloroformic solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer, and then the pyridine (Beijing Chemical Plant of adding 0.5mL, analytical pure), 0 ℃ of lower reaction 6 hours, obtain the hydroxypropylβ-cyclodextrin-poly(lactic acid) of yellow transparent-4-oil of mirbane chloro-formic ester graftomer crude product in solution.This crude product in solution is removed chloroform at 15 ℃ of lower rotary evaporations, then in 100mL ether/sherwood oil (volume ratio is 2:1) mixing solutions precipitation, and wash (60mL * 3 time) with ether/sherwood oil (volume ratio is 2:1) mixing solutions.With the purified product that obtains in 25 ℃ of vacuum drying ovens dry 24 hours, obtain yellow solid product hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester graftomer 1.96 grams.
(3) 1.0g hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester graftomer is joined in the chloroform of 4mL the chloroformic solution of preparation hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester; DPPE (the Avanti company that in the 6mL chloroform, adds 0.2g, 97%), the chloroformic solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) of the triethylamine of 0.05mL and 4mL-4-oil of mirbane chloro-formic ester, at 25 ℃, the lucifuge reaction is 20 hours under the nitrogen, crude product in solution is removed chloroform at 15 ℃ of lower rotary evaporations, then in 100mL ether/sherwood oil (volume ratio is 1:1) mixing solutions precipitation, and wash (60mL * 3 time) with ether/sherwood oil (volume ratio is 1:1) mixing solutions.With the purified product that obtains in 25 ℃ of vacuum drying ovens dry 24 hours, obtain hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester-DPPE graftomer crude product 1.02 grams.
Adding the described hydroxypropylβ-cyclodextrin-poly(lactic acid) of 0.75g-4-oil of mirbane chloro-formic ester-DPPE graftomer crude product to 50mL pH is in 8.5 the Tris-HCl buffered soln, 20 ℃ of lucifuge reactions 16 hours under nitrogen, then in dialysis tubing, the lucifuge dialysis obtained the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer 0.67 gram behind the purifying in 48 hours in 20 ℃ of distilled water of 1L.The final product lyophilize is preserved.
(4) hydroxypropylβ-cyclodextrin-poly(lactic acid) behind the 0.2g purifying-DPPE graftomer is dissolved in the N of 6ml, dinethylformamide (Beijing Chemical Plant, analytical pure) in, drip in the 14ml deionized water when stirring, the band blue light emulsion that forms, this emulsion is packed in the dialysis tubing, put into 3 liters of deionized waters dialysis and obtained hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle in 48 hours.
After testing, the weight-average molecular weight of resulting hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer is 46006Da.
All other detect collection of illustrative plates and see Fig. 1 to Fig. 7.Wherein, Fig. 1 represents the transmission electron microscope picture of the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle among the embodiment 1.As can be seen from the figure 1, hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle has regular spheroidal structure.
Fig. 2 represents the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle scattering of light synoptic diagram among the embodiment 1.
The infrared spectrogram of the hydroxypropylβ-cyclodextrin among Fig. 3 (a) expression embodiment 1.The infrared spectrogram of the hydroxypropylβ-cyclodextrin among Fig. 3 (b) expression embodiment 1-poly(lactic acid) graftomer.The infrared spectrogram of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 3 (c) expression embodiment 1-4-oil of mirbane chloro-formic ester graftomer.The infrared spectrogram of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 3 (d) expression embodiment 1-DPPE graftomer.
Compare with Fig. 3 (a), Fig. 3 (b) is at 1754cm
-1Near new absorption peak of appearance, this is the stretching vibration peak of the ester carbonyl group (C=O) in the poly(lactic acid) branch.Fig. 3 (a) is at 3401cm
-1Very strong vibrational frequency is arranged, and after poly(lactic acid) in the grafting, peak herein obviously weakens, and has illustrated that also reaction has occured for hydroxypropylβ-cyclodextrin and rac-Lactide simultaneously; Compare the 3080cm of Fig. 3 (c) with Fig. 3 (b)
-1Be the flexural vibration peak of-OH, 4-oil of mirbane chloro-formic ester absorption peak (1754cm
-1) and poly(lactic acid) branch in the stretching vibration peak overlapping of ester carbonyl group (C=O), the 2730cm of Fig. 3 (d)
-1Stretching vibration peak for P-OH.This shows, adopt method preparation of the present invention can obtain target compound hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE.
The proton nmr spectra of the hydroxypropylβ-cyclodextrin among Fig. 4 (a) expression embodiment 1; The proton nmr spectra of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 4 (b) expression embodiment 1-DPPE graftomer; The carbon-13 nmr spectra of the hydroxypropylβ-cyclodextrin among Fig. 4 (c) expression embodiment 1; The carbon-13 nmr spectra of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 4 (d) expression embodiment 1-DPPE graftomer.
Same Fig. 4 (a) compares, among Fig. 4 (b)～0.82ppm and～signal at 1.54ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer in terminal-CH in the DPPE segment
3On the proton uptake peak and polylactic acid chain segment in-CH
3On the proton uptake peak, 3.05～3.24ppm and 6.7～7.2ppm place signal corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer-CH
2Proton uptake peak (CH
2,-OOCCH
2,-CH
2Among-the OOC-CH
2The peak); The signal at～5.24ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer on the polylactic acid chain segment in the repeating unit-CH and DPPE segment in-the proton uptake peak of CH; The signal at～8.03ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer-the proton uptake peak of NH.
Same Fig. 4 (c) compares, Fig. 4 (d) the signal at～8.7ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer in terminal-CH on the DPPE segment
3C on absorption peak, the signal at～16.9ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer in CH on the DPPE segment
3CH
2-in-CH
2The absorption peak of upper C, the signal at～77.5ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer in the poly(lactic acid) repeating unit-CH-on the absorption peak of C, the signal at～170ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer on the absorption peak of C on the C=O.The signal at～47.3ppm place corresponding to hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer on the DPPE segment-H
2Among the C-NH--CH
2The absorption peak of upper C.
The nucleus magnetic resonance phosphorus spectrogram of the DPPE among Fig. 5 (a) expression embodiment 1; The nucleus magnetic resonance phosphorus spectrogram of the hydroxypropylβ-cyclodextrin-poly(lactic acid) among Fig. 5 (b) expression embodiment 1-DPPE graftomer.
From Fig. 5 (a) Fig. 5 (b), can see hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer
31The PNMR chemical shift is at 0.62ppm, and independent DPPE
31The P chemical shift this shows at-1.22ppm, adopts method of the present invention to prepare target compound hydroxypropylβ-cyclodextrin-poly(lactic acid)-phosphatidylethanolamine graftomer.
Fig. 6 represents the fluorescence spectrum figure of the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle among the embodiment 1, its in 6 a-f represent respectively the fluorescence emission spectrum of pyrene in the aqueous solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) that concentration is 0.001mg/ml, 0.0004mg/ml, 0.0002mg/ml, 0.00008mg/ml, 0.00002mg/ml, 0.000001mg/ml-DPPE graftomer.
Fig. 7 represents the micelle-forming concentration figure of the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle among the embodiment 1.
By Fig. 6 and Fig. 7 as can be known, size of particles is at 134 ± 13nm; The micelle-forming concentration of fluorescence spectrometry micella is 5.0 * 10
-4Mg/ml.
Synthesizing of hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer
(1) with rac-Lactide (the Alfar Aesar company of 5.64g; 97%; analytical pure) and the hydroxypropylβ-cyclodextrin of 2.5g (Japanese Sigma-Aldrich company) place there-necked flask; after vacuumizing 1 hour, the dmso solution after the distillation of adding 10mL adds 0.5mL triethylamine (chemical plant, Gansu Province, west, Shantou, Guangdong city; analytical pure); at 80 ℃, reaction is 12 hours under the nitrogen protection, obtains hydroxypropylβ-cyclodextrin-thick product of poly(lactic acid) graftomer.Then precipitate with 200mL water, washing (100mL * 4 time), drying is 48 hours in 20 ℃ of vacuum drying oven casees, and then with toluene extracting (20mL * 2 time), drying is 48 hours in 20 ℃ of vacuum drying ovens, obtain solid product hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer 6.11g, as calculated n=14.
(2) hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer 2g is joined in the 9mL chloroform chloroformic solution of preparation hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer; The 4-oil of mirbane chloro-formic ester (Alfar Aesar company, 97%) of 0.1g and the DMAP (Alfar Aesar company, 99%) of 0.1g are dissolved preparation 4-oil of mirbane chloro-formic ester and DMAP chloroformic solution with the 9mL chloroform; The 4-oil of mirbane chloro-formic ester of 9mL and the mixing chloroformic solution of DMAP are added drop-wise in the chloroformic solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer, and then the pyridine (Beijing Chemical Plant of adding 1mL, analytical pure),-10 ℃ of lower reactions 10 hours, obtain the hydroxypropylβ-cyclodextrin-poly(lactic acid) of yellow transparent-4-oil of mirbane chloro-formic ester graftomer crude product in solution.This crude product in solution is removed chloroform at 20 ℃ of lower rotary evaporations, then in 150mL ether/sherwood oil (volume ratio is 1:1) mixing solutions precipitation, and wash (40mL * 3 time) with ether/sherwood oil (volume ratio is 1:1) mixing solutions.With the purified product that obtains in 20 ℃ of vacuum drying ovens dry 48 hours, obtain yellow solid product hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester graftomer 1.8 grams.
(3) 0.9g hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester graftomer is joined in the chloroform of 6mL the chloroformic solution of preparation hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester; DPPE (the Avanti company that in the 6mL chloroform, adds 0.03g, 97%), the chloroformic solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) of the triethylamine of 0.15mL and 6mL-4-oil of mirbane chloro-formic ester, at 20 ℃, the lucifuge reaction is 15 hours under the nitrogen, crude product in solution is removed chloroform at 20 ℃ of lower rotary evaporations, then in 50mL ether/sherwood oil (volume ratio is 1:1) mixing solutions precipitation, and wash (40mL * 3 time) with ether/sherwood oil (volume ratio is 1:1) mixing solutions.With the purified product that obtains in 20 ℃ of vacuum drying ovens dry 48 hours, obtain hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester-DPPE graftomer crude product 0.79 gram.
The pH that adds the crude product of the described hydroxypropylβ-cyclodextrin-poly(lactic acid) of 0.6g-4-oil of mirbane chloro-formic ester-DPPE graftomer to 30mL is in 8 the Tris-HCl buffered soln, 4 ℃ of lucifuge reactions 20 hours under nitrogen, then in dialysis tubing, the lucifuge dialysis obtained the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer 0.54 gram behind the purifying in 24 hours in 4 ℃ of distilled water of 1L.The final product lyophilize is preserved.
(4) hydroxypropylβ-cyclodextrin-poly(lactic acid) behind the 0.2g purifying-DPPE graftomer is dissolved in the N of 6ml, dinethylformamide (Beijing Chemical Plant, analytical pure) in, drip in the 14ml deionized water when stirring, the band blue light emulsion that forms, this emulsion is packed in the dialysis tubing, put into 3 liters of deionized waters dialysis and obtained polymer nano-particle in 48 hours.
After testing, the weight-average molecular weight of resulting hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer is 6464Da.All other corresponding collection of illustrative plates that detect collection of illustrative plates and embodiment 1 are similar.Hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle has regular ball structure; Size of particles is at 125 ± 11nm; The micelle-forming concentration of fluorescence spectrometry micella is 6.58 * 10
-4Mg/ml.
Synthesizing of hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer
(1) with rac-Lactide (the Alfar Aesar company of 16.92g; 97%; analytical pure) and the hydroxypropylβ-cyclodextrin of 0.5g (Japanese Sigma-Aldrich company) place there-necked flask; after vacuumizing 1 hour, the dmso solution after the distillation of adding 50mL adds 2mL triethylamine (chemical plant, Gansu Province, west, Shantou, Guangdong city; analytical pure); at 82 ℃, reaction is 11 hours under the nitrogen protection, obtains hydroxypropylβ-cyclodextrin-thick product of poly(lactic acid) graftomer.Then precipitate with 500mL water, washing (200mL * 3 time), drying is 40 hours in 30 ℃ of vacuum drying oven casees, and then with toluene extracting (50mL * 2 time), drying is 40 hours in 30 ℃ of vacuum drying ovens, obtain solid product hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer 13.07g, as calculated n=210.
(2) hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer 1.8g is joined in the 3mL chloroform chloroformic solution of preparation hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer; The 4-oil of mirbane chloro-formic ester (Alfar Aesar company, 97%) of 0.18g and the DMAP (Alfar Aesar company, 99%) of 0.03g are dissolved preparation 4-oil of mirbane chloro-formic ester and DMAP chloroformic solution with the 3mL chloroform; The 4-oil of mirbane chloro-formic ester of 3mL and the mixing chloroformic solution of DMAP are added drop-wise in the chloroformic solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) graftomer, then pyridine (the Beijing Chemical Plant that adds 2mL, analytical pure),-5 ℃ of lower reactions 8 hours, obtain the hydroxypropylβ-cyclodextrin-poly(lactic acid) of yellow transparent-4-oil of mirbane chloro-formic ester graftomer crude product in solution.This crude product in solution is removed chloroform at 25 ℃ of lower rotary evaporations, then in 200mL ether/sherwood oil (volume ratio is 3:1) mixing solutions precipitation, and wash (100mL * 3 time) with ether/sherwood oil (volume ratio is 3:1) mixing solutions.With the purified product that obtains in 30 ℃ of vacuum drying ovens dry 36 hours, obtain yellow solid product hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester graftomer 1.62 grams.
(3) 1.5g hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester graftomer is joined in the chloroform of 8mL the chloroformic solution of preparation hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester; DPPE (the Avanti company that in the 8mL chloroform, adds 0.03g, 97%), the chloroformic solution of hydroxypropylβ-cyclodextrin-poly(lactic acid) of the triethylamine of 0.3mL and 8mL-4-oil of mirbane chloro-formic ester, at 30 ℃, the lucifuge reaction is 17 hours under the nitrogen, crude product in solution is removed chloroform at 25 ℃ of lower rotary evaporations, then in 250mL ether/sherwood oil (volume ratio is 2:1) mixing solutions precipitation, and wash (100mL * 3 time) with ether/sherwood oil (volume ratio is 2:1) mixing solutions.With the purified product that obtains in 30 ℃ of vacuum drying ovens dry 36 hours, obtain hydroxypropylβ-cyclodextrin-poly(lactic acid)-4-oil of mirbane chloro-formic ester-DPPE graftomer crude product 1.3 grams.
The pH that adds the described hydroxypropylβ-cyclodextrin-poly(lactic acid) of 1.2g-4-oil of mirbane chloro-formic ester-DPPE graftomer crude product to 10mL is in 9 the Tris-HCl buffered soln, 25 ℃ of lucifuge reactions 15 hours under nitrogen, then in dialysis tubing, the lucifuge dialysis obtained the hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer 1.08 grams behind the purifying in 36 hours in 25 ℃ of distilled water of 1L.The final product lyophilize is preserved.
(4) hydroxypropylβ-cyclodextrin-poly(lactic acid) behind the 0.2g purifying-DPPE graftomer is dissolved in the N of 6ml, dinethylformamide (Beijing Chemical Plant, analytical pure) in, drip in the 14ml deionized water when stirring, the band blue light emulsion that forms, this emulsion is packed in the dialysis tubing, put into 3 liters of deionized waters dialysis and obtained hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle in 48 hours.
After testing, the weight-average molecular weight of resulting hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer is 65557Da.All other corresponding collection of illustrative plates that detect collection of illustrative plates and embodiment 1 are similar.Hydroxypropylβ-cyclodextrin-poly(lactic acid)-DPPE graftomer nanoparticle has regular ball structure; Size of particles is at 141 ± 8nm; The micelle-forming concentration of fluorescence spectrometry micella is 3.45 * 10
-4Mg/ml.
Claims (10)
1. a cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer is characterized in that, the structural formula of described cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer is as shown in the formula shown in (1),
M is the integer of 6-8 in the formula (1), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, E are the structure by following formula (2) expression,
L is that R and R ' represent that all carbonatoms is the alkyl of 5-21 by the aliphatic poly ester structure of formula (3), formula (4) or formula (5) expression in the formula (2), and R and R ' are identical or different,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240.
2. cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer according to claim 1, wherein, the weight-average molecular weight of described cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer is 4000-100000Da.
3. cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer according to claim 1, wherein, described cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer is that particle diameter is the nanoparticle of 80-150nm.
4. the preparation method of cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer claimed in claim 1 is characterized in that, the method may further comprise the steps:
(a) in the presence of organic amine, in the first organic solvent, ester is contacted with cyclodextrin, obtain by the cyclodextrin shown in the formula (6)-aliphatic polyester graftomer, described cyclodextrin is to be selected from a kind of in alpha-cylodextrin, beta-cyclodextrin, hydroxypropylβ-cyclodextrin or the γ-cyclodextrin, described ester is one or both in rac-Lactide, glycollide and the caprolactone
M is the integer of 6-8 in formula (6), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, L are the aliphatic poly ester structure by formula (3), formula (4) or formula (5) expression,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240;
(b) in the presence of nitrogenous heteroatomic 6-membered heterocyclic compound, in the second organic solvent, described cyclodextrin-aliphatic polyester graftomer is contacted with 4-oil of mirbane chloro-formic ester, obtain by the cyclodextrin-aliphatic polyester shown in the formula (7)-4-oil of mirbane chloro-formic ester graftomer
M is the integer of 6-8 in formula (7), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, L are that A is the structure by formula (8) expression by the aliphatic poly ester structure of formula (3), formula (4) or formula (5) expression,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240;
(c) under the existence of organic amine, in the 3rd organic solvent, after making described cyclodextrin-aliphatic polyester-4-nitrobenzene chloro-formate graft polymers and phosphatidyl-ethanolamine contacting, products therefrom is contacted with Tri(Hydroxymethyl) Amino Methane Hydrochloride cushioning liquid, obtain by the cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer shown in formula (1), described phosphatidyl-ethanolamine is to be selected from a kind of in DPPE, two grease acyl phosphatidyl-ethanolamines or DSPE
M is the integer of 6-8 in the formula (1), G be Sauerstoffatom or-O-CH
2-CH (CH
3)-O-, E are the structure by following formula (2) expression,
L is that R and R ' represent that all carbonatoms is the alkyl of 5-21 by the aliphatic poly ester structure of formula (3), formula (4) or formula (5) expression in the formula (2), and R and R ' are identical or different,
N is the integer of 12-240 in the formula (3), and z is the integer of 6-120 in the formula (4), and x is the integer of 12-240 in the formula (5), and y is the integer of 12-240.
5. preparation method according to claim 4, wherein, described organic amine is triethylamine, described the first organic solvent is dimethyl sulfoxide (DMSO), described nitrogenous heteroatomic 6-membered heterocyclic compound is DMAP and pyridine, described the second organic solvent is chloroform or methylene dichloride, and described the 3rd organic solvent is chloroform or methylene dichloride.
6. preparation method according to claim 4, wherein, described contact in the step (a) is carried out under inert atmosphere, the condition of described contact comprises: the mol ratio of described ester and described cyclodextrin is 1-15:1, with respect to the 1g cyclodextrin, the consumption of described organic amine is 0.01-5ml, and the consumption of described the first organic solvent is 4-100ml, the temperature of contact is 70-85 ℃, and the time of contact is 10-15 hour.
7. preparation method according to claim 4, wherein, in the step (b), described nitrogenous heteroatomic 6-membered heterocyclic compound is DMAP and pyridine, the condition of described contact comprises: the weight ratio of described cyclodextrin-aliphatic polyester graftomer and described 4-oil of mirbane chloro-formic ester is 5-20:1, the weight ratio of described cyclodextrin-aliphatic polyester graftomer and described DMAP is 20-60:1, with respect to the described cyclodextrin of 1g-aliphatic polyester graftomer, the consumption of described pyridine is 0.2-2ml, the consumption of described the second organic solvent is 3-12ml, the temperature of contact is-10 ℃ to 0 ℃, and the time of contact is 6-10 hour.
8. preparation method according to claim 4, wherein, described contact in the step (c) all is that lucifuge is carried out under inert atmosphere, the condition that cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer contacts with phosphatidylethanolamine comprises: the weight ratio of described cyclodextrin-aliphatic polyester-4-oil of mirbane chloro-formic ester graftomer and described phosphatidylethanolamine is 5-50:1, with respect to the described cyclodextrin-aliphatic polyester of 1g-4-oil of mirbane chloro-formic ester graftomer, the consumption of described organic amine is 0.05-0.3ml, the consumption of described the 3rd organic solvent is 8-18ml, the temperature of contact is 20-30 ℃, and the time of contact is 15-20 hour;
With respect to the described product of 1g, the pH of described Tri(Hydroxymethyl) Amino Methane Hydrochloride buffered soln is 8-9, and consumption is 8-70ml, and the temperature that products therefrom contacts with Tri(Hydroxymethyl) Amino Methane Hydrochloride buffered soln is 4-25 ℃, and the time of contact is 15-20 hour.
9. preparation method according to claim 4, wherein, comprise also that in step (a) the first organic solvent in the products therefrom was removed after described ester contacted with cyclodextrin, the product that to remove afterwards behind the first organic solvent precipitates in water, obtain solid product, again the gained solid product is washed successively with drying after again with toluene or benzene extracting, with the solid after the extracting at 20-30 ℃ of lower vacuum-drying 24-48 hour;
Comprise also that in step (b) the second organic solvent in the products therefrom was removed after described cyclodextrin-aliphatic polyester graftomer contacted with 4-oil of mirbane chloro-formic ester, the product that to remove afterwards behind the second organic solvent precipitates in ether/sherwood oil mixing solutions, obtain solid product, again the gained solid product is washed with ether/sherwood oil mixing solutions, at 20-30 ℃ of lower vacuum-drying 24-48 hour;
In step (c), also comprise the second organic solvent in the described product is removed, the product that to remove afterwards behind the second organic solvent precipitates in ether/sherwood oil mixing solutions, obtain solid product, again with the gained solid product at 20-30 ℃ of lower vacuum-drying 24-48 hour.
10. preparation method according to claim 9 wherein, also comprises in step (c) lucifuge in 4-25 ℃ distilled water of the cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer after the vacuum-drying was dialysed 24-48 hour.
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| CN108329660B (en) * | 2017-01-20 | 2020-09-29 | 深圳市虹彩新材料科技有限公司 | Beta-cyclodextrin graft and preparation method and application thereof |
| CN108478532B (en) * | 2018-04-23 | 2020-12-15 | 滨州医学院 | Preparation method of beta cyclodextrin-dipalmitoliposome and application of beta cyclodextrin-dipalmitoliposome as drug carrier |
| CN108478533B (en) * | 2018-04-23 | 2020-12-08 | 滨州医学院 | Preparation method of beta cyclodextrin-LPC liposome and application of beta cyclodextrin-LPC liposome as drug carrier |
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| US5208316A (en) * | 1990-10-01 | 1993-05-04 | Toppan Printing Co., Ltd. | Cyclodextrin polymer and cyclodextrin membrane prepared using said polymer |
| CN1663967A (en) * | 2005-02-21 | 2005-09-07 | 山东大学 | Oligo-lactic acid based cyclodextrin derivatives and method for preparing same |
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| CN101392034A (en) * | 2007-09-18 | 2009-03-25 | 国家纳米科学中心 | Dextran-phosphatidyl ethanolamine polymer micelle and preparation method thereof |
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| US5208316A (en) * | 1990-10-01 | 1993-05-04 | Toppan Printing Co., Ltd. | Cyclodextrin polymer and cyclodextrin membrane prepared using said polymer |
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| CN101392034A (en) * | 2007-09-18 | 2009-03-25 | 国家纳米科学中心 | Dextran-phosphatidyl ethanolamine polymer micelle and preparation method thereof |
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